In 2014, an estimated 232,000 women in the United States will be diagnosed with breast cancer. Three- fourths will have no known heritable susceptibility, suggesting that environments and individual behaviors play a substantial role in breast carcinogenesis. The existence of breast cancer intrinsic subtypes adds to the difficult task of understanding breast cancer etiology, as each subtype is hypothesized to have a distinct risk factor profile. In addition, aggressive subtypes are important focal points for risk factor identification and risk reduction strategies since these tumors often do not benefit from available targeted therapies and are associated with higher mortalities. Researchers have proposed smoking as a probable risk factor for breast cancer based on epidemiologic findings and the detection of nicotine and cigarette byproducts (e.g., DNA adducts) in breast tissues of smokers. Contemporary in vitro studies of breast epithelium treated with nicotine have demonstrated increased rates of cell proliferation through over activation of the epidermal growth factor receptor (EGFR), thereby establishing a measurable biologic endpoint to test the hypothesis that smoking - and concomitant nicotine exposure - is associated with EGFR positive (EGFR+) breast cancer. Defined by immunohistochemical staining in greater than ten percent of examined tumor cells, EGFR-positivity is a poor prognostic marker and is most common among African American (AA) patients. In vitro studies have also shown that nicotine-induced breast carcinogenesis is mediated by the a-9 subunit of the nicotinic acetylcholine receptor (nAChR). Moreover, if nAChR mediates smoking-related breast carcinogenesis in vivo, it is conceivable that smoking interaction with genetic variants of the nAChR a-9 subunit may be associated with differential risk of EGFR+ breast cancer. This research training plan and novel study resource will allow the fellowship applicant to establish a foundation in theories of carcinogenesis and gain expertise in molecular epidemiologic methods needed to examine the hypothesis that nicotine exposure confers an increased risk of EGFR+ breast cancer. Aim 1: Using smoking status as a proxy for nicotine exposure in vivo, we will examine the relationship between smoking and EGFR+ breast cancer. We will use parametric latency functions to identify time frames during a woman's lifetime where smoking is associated with the greatest risk of EGFR+ breast cancer. Aim 2: We will also examine whether smoking interaction with common variants of the nAChR a-9 subunit confers differential risk of EGFR+ breast cancer; this interaction will be assessed using single nucleotide polymorphisms of its encoding gene, CHRNA9, as surrogates for variations in protein function. The AMBER project is a consortium of four studies of AA women, including 5,739 breast cancer cases and 14,273 controls with self-reported data on environmental exposures, DNA obtained from saliva or blood specimens, and tumor samples. This consortium provides an idea study population to examine the etiology of EGFR+ breast cancer since EGFR-positivity is most common among AA patients.